Transmetalations from zirconium to copper intermediates

ABSTRACT

Higher order cuprate complexes are prepared by means of a transmetalation from a corresponding zirconate intermediate. This process is particularly valuable with respect to the preparation of vinylic side chains such as are present in prostaglandins, as it is possible in accordance with the present invention to proceed directly from the acetylenic precursors via the reactive cuprates to the desired final products in a one-pot operation without isolation of intermediates and in high yields. Sequential additions to zirconium intermediates of components which together comprise the cuprate involved in transmetalation with the zirconium intermediate are disclosed as alternative procedures.

This invention was made with Government support under Grant/Contract No.CHE 87-03757 awarded by the National Science Foundation. The Governmenthas certain rights in this invention.

BACKGROUND OF THE INVENTION

This invention relates to the field of organometallic chemistry. Inparticular, this invention relates to methods for the preparation oforganometallic complexes useful as reactive intermediates in organicsynthesis, especially for the formation of carbon-to-carbon bonds.

The utility of organocopper complexes as reactive intermediates in avariety of synthetic reactions has been well known for decades.Particularly important reactions utilizing organocopper complexes in theformation of carbon-to-carbon bonds include addition reactions (such as1,4-conjugate additions and carbocupration reactions) and substitutionreactions (such as, for example, the displacement of halides, tosylatesor mesylates and ring opening of epoxides). In such reactions, theorganocopper complex formally serves as the source of a suitablecarbanion for introduction into a target molecule by addition ordisplacement.

Early work in the field of organocopper chemistry involved treatment ofeither catalytic or stoichiometric quantities of a copper(I) halide witha Grignard (RMgX) or organolithium (RLi) reagent. The resultant productsare either neutral organocopper reagents RCu(I) or copper(I) monoanionicsalts R₂ CuM (M=Li or MgX), commonly referred to as lower order orGilman reagents. Copper(I) cyanide is also an excellent precursor forthe direct formation of lower order cyanocuprates RCu(CN)Li upontreatment with an equivalent of an organolithium. It is believed thatthe strength of the Cu-CN linkage accounts for the direct cuprateformation with one equivalent of the organolithium, rather than themetathesis that occurs with copper(I) halides to produce an equivalentof LiX.

While such lower order complexes have some direct syntheticapplications, it has further been determined that reagents of this typecan be composed of different ligands (i.e., R≠R'). In other words,rather than forming a complex of the formula R₂ CuLi from twoequivalents of the same RLi, different organolithium compounds can beused to provide a complex of the formula R_(T) R_(R) CuLi. In thismanner, it is possible to conserve potentially valuable R_(T) Li.Successful exploitation of such complexes comprising two differentligands is based on the ability to control the selectivity of transferof the desired ligand R_(T) rather than the residual (or "dummy") groupR_(R) from copper to electrophilic carbon.

A particularly significant advance in the field of organocoppercomplexes has been the development of so-called "higher order" cuprates.For example, the admixture of two equivalents of RLi (or one equivalenteach of R_(T) Li and R_(R) Li) with copper(I) cyanide proceeds to theformation of a copper(I) dianionic complex or higher order cyanocuprate,R₂ Cu(CN)Li₂. The cyano ligand, with its π-acidic nature, is believed toenable the copper to accept a third negatively-charged ligand inethereal solvents (e.g., Et₂ O and THF). Such higher order complexes,particularly those derived from two different organolithium compounds,have been successfully exploited as highly selective and efficient meansof making key carbon-to-carbon bonds.

The use of cuprates in 1,4-conjugate addition reactions for introductionof unsaturated carbanions is especially attractive due to the completecontrol of double bond geometry in the reaction scheme. This is ofparticular significance, for example, in the synthesis of variousprostaglandins via conjugate addition of an alkenyl moiety to theunsaturated ketone functionality of a substituted cyclopentenone.

To date, the preparation of reactive vinylic organocuprate reagents hasinvolved a limited number of typical reaction pathways. In particular,for transfer of a particular alkenyl side chain to a target molecule,either a vinylic halide (usually, the bromide or iodide) or a vinylicstannane has usually been employed as a precursor molecule. Theseprecursor molecules are generally prepared from a correspondingacetylene and converted to the reactive copper reagents for use assynthetic intermediates.

U.S. Pat. No. 4,777,275 to Campbell et al., the disclosure of which ishereby incorporated by reference, describes a process for preparing ahigher order copper complex in which a ligand (designated R_(t)) whichis desired in a subsequent synthetic organic reaction to form a newcarbon-to-carbon bond is transferred in situ from a stannane compound toa first higher order copper complex to form a second higher order coppercomplex including the ligand. Of course, to employ this method it isfirst necessary to prepare specific vinyl stannanes by art recognizedtechniques. Such techniques generally call for the reaction of asuitable acetylene with, e.g., a trialkyl tin hydride. Unfortunately,the stannanes are generally quite toxic. Therefore, it would beadvantageous to avoid such intermediates entirely if possible.

Preparation of suitable cuprate complexes from the corresponding halidesis also problematic, particularly in the case of alkenylhalides.Formation of the desired cuprates is generally effected from thecorresponding alkenyllithium compounds, which in turn are prepared bymetal-halogen exchange (typically using two equivalents of highlypyrophoric and expensive t-butyllithium) with the correspondingalkenylhalides or reaction of the halides with lithium metal.Preparation of the organolithium precursors via this latter method istypically tedious, and may result in low yields. Moreover, in the caseof the alkenyl compounds, there may be some loss of double-bondstereochemistry.

According to U.S. Pat. No. 4,415,501 to Grudzinskas et al., thedisclosure of which is also hereby incorporated by reference, some ofthe potentially problematic issues associated with the chemistryinvolved in the formation of vinylic cuprate complexes are avoided byutilizing an alternative class of reagents. A class of alkenylzirconiumreagents are described, which may be employed directly in variousconjugate addition reactions. These alkenylzirconium reagents areprepared by reaction of the corresponding protected alkynol withdicyclopentadienyl zirconium chlorohydride; the latter is typicallygenerated in situ by the reduction of dicyclopentadienyl zirconiumdichloride in solution under an inert atmosphere. The thus-preparedalkenylzirconium reagents are described as moisture sensitive, and thusit is suggested that they are best prepared just prior to use. Reactionof the alkenylzirconium reagents with the target molecule for aconjugate addition is effected in the presence of a catalytic amount ofa reduced nickel catalyst.

While the method of U.S. Pat. No. 4,415,501 obviates some of thepotential problems associated with the formation of the reactivecuprates, it does so at the cost of yield and purity of the resultantproducts, as is immediately apparent from a review of Table II of thereference. Indeed, while the products of hydrozirconation reactions maybe utilized in selected coupling reactions to form carbon-to-carbonbonds, there is no general established method for directly transferringthese ligands to alpha, beta unsaturated ketones in a conjugate (i.e.,1,4-) sense. Therefore, the reference method using organozirconiumcompounds directly as reagents is limited in applicability and clearlyunacceptable for the preparation of most products, in particular fromrelatively expensive optically-active intermediates, on a commercialscale.

It is an object of the present invention to provide a method for thepreparation of suitable organometallic intermediates for use in thetransfer of a particular carbanion equivalent (e.g., a vinylicorganometallic species) to a target molecule with the formation ofcarbon-to-carbon bonds pursuant to the heretofore known reactionmechanisms involving such carbanions.

In particular, it is an object of the present invention to provide amethod for the preparation of reactive organometallic intermediateswhich results in a high yield of both the intermediates and of the finalproducts prepared via such intermediates.

In addition, it is a further object of the present invention to providea method for the preparation of reactive organometallic intermediatesfor use in the preparation of a variety of products exploiting knownreaction mechanisms formally involving carbanions (such as 1,4-conjugateadditions or displacement reactions) without the need to prepare orisolate halide or stannane precursors of the subject organometallics.

SUMMARY OF THE INVENTION

In accordance with the present invention, higher order cuprate complexesof the type described in, e.g., U.S. Pat. No. 4,785,124 to Campbell etal., are prepared by means of a transmetalation from a correspondingzirconate intermediate. This process is particularly valuable withrespect to the preparation of vinylic side chains such as are present inprostaglandins, as it is possible in accordance with the presentinvention to proceed directly from the acetylenic precursors via thereactive cuprates to the desired final products in a one-pot operationwithout isolation of intermediates and in high yields. Thus, theproblems associated with the preparation of the corresponding vinylhalides or stannanes are avoided entirely.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a novelmethod for the preparation of a cuprate complex of the general formula I##STR1## wherein R_(T) is a ligand (as hereinafter defined) which willparticipate in carbon-to-carbon bond formation; R¹ is different fromR_(T) and is selected from the group consisting of alkyl, alkenyl,alkynyl, allylic, aryl, benzylic and heterocyclic moieties, --BR³wherein B is O or S and R³ is an alkyl, alkenyl, alkynyl, allylic, aryl,benzylic or heterocyclic moiety, and --NR⁴ R⁵ wherein R⁴ and R⁵ are thesame or different and each is an alkyl, alkenyl, alkynyl, allylic, aryl,benzylic or heterocyclic moiety, said moieties being unsubstituted orsubstituted by non-interfering substituents; and A is CN or SCN.

In accordance with the method of the present invention, a zirconiumintermediate of general formula II ##STR2## wherein Cp represents acyclopentadienyl moiety which is unsubstituted or substituted bynon-interfering substituents (e.g., pentamethylcyclopentadienyl), X ishalogen (e.g., Cl, Br, I) and R_(T) is as previously defined, is treatedby addition of a compound of general formula R² M (e.g., R² Li or R²MgX), wherein M is a suitable metal, X is halogen and R² is defined inthe same manner as R¹ and may be the same as or different from R¹, toprepare an intermediate of general formula III wherein R_(T) and R² areas previously defined.

Without isolation, the intermediate of general formula III is reacted inaccordance with a preferred embodiment of the inventive method with astable, storable cuprate reagent of formula R¹ ₂ Cu(A)Li₂, wherein R¹and A are as previously defined, to provide the compound of generalformula I via transmetalation from the zirconium intermediate in veryhigh yield.

As an alternative to the above procedure (designated as reaction path Ain Scheme 1), pursuant to one alternative the higher order cuprate I maybe realized by sequential additions of the elements of R¹ ₂ Cu(A)Li₂.For purposes of clarity, the following discussion will refer to R',defined in the same manner as R¹. As R'₂ Cu(A)Li₂ is composed of 2 R'Liplus Cu(A), cuprate I can be prepared via addition of two equivalents ofR'Li to intermediate II, followed by introduction of one equivalent ofR'Cu(A)Li, as illustrated in reaction path B in Scheme 1. Yet anothervariant procedure calls for addition of three equivalents of R'Li tozirconate II, followed by one equivalent of Cu(A), the latter as a solidor in a LiX-solubilized form [e.g., Cu(A).nLiX, wherein n is an integerfrom 1 to 10] in solution in an ethereal solvent as per reaction path Cin Scheme 1. As all of these alternatives proceed from the zirconate II,and as the overall reaction pursuant to each alternative is believed toinvolve at least some transmetalation from zirconium to copper, thesealternatives are all viewed as aspects of the present invention.

Moreover, it is clearly not essential that, ultimately, threeequivalents of the same R'Li be used; various combinations oforganolithium reagents are acceptable. This is illustrated in Scheme 2,wherein the use of up to three different reagents is contemplated. Eachof R', R" and R'" is a group falling within the definition previouslygiven for R¹ ; while any two or all three of R', R" and R'" may be thesame, all three may be different. As according to Scheme 2 a variety ofzirconates and cuprates may be formed, the various products aredesignated using groups R^(A), R^(B) and R^(C), each of whichcorresponds to one of R', R" and R'" in the starting materials. In thefinal product of general formula I, R¹ thus corresponds to one of R', R"and R'".

In terms of mechanism, it is not presently known precisely how zirconateIII and a higher order cuprate exchange ligands to provide the productof general formula I. Initially, it is believed that addition of a firstequivalent of R'Li to intermediate II produces zirconate III via asimple transmetalation from lithium to zirconium. Under the influence ofexcess R'Li, however, other events may well take place, leading to a mixof discrete organolithium reagents prior to introduction of any sourceof Cu(I), such as R'Cu(A)Li, Cu(A) or Cu(A).nLiX. Depending on thenature of R'Li, addition of >1 equivalent of R'Li to zirconate II maywell establish an equilibrium including free R_(T) Li, as shown below:##STR3## Although not yet proven, it has been suggested that such aphenomenon may occur [Negishi, E. et al., Aldrichimica Acta 18, 31(1985)]. The extent of the equilibrium giving rise to R_(T) Li, if itexists at all, is not predictable. Irrespective of such a potentialequilibrium, the thermodynamic sink for the overall process ultimatelyplaces the R_(T) ligand on copper, whether via direct ligand exchangebetween intermediate III and a higher order cuprate, or by cuprateformation using equilibria-generated R_(T) Li and an alternate Cu(I)source. Representative procedures are described infra (see Example 4,relating to Scheme 1, path B and Example 5, relating to Scheme 1, pathC) which establish unequivocally that the order of mixing is irrelevantto the net transmetalation scheme leading to cuprate I. ##STR4##

The resultant solution containing the compound of general formula I maybe used directly in subsequent reactions (such as, e.g., conjugateadditions or displacement reactions) to transfer the ligand R_(T) to thetarget molecule in very high yields. The product may then be recoveredusing known methods. All reactions are preferably carried out under aninert atmosphere (e.g., argon).

In accordance with a preferred embodiment of the inventive method, thezirconium intermediate of general formula II is prepared in a mannerknown per se by a hydrozirconation reaction which comprises reacting asuitable ligand precursor compound (as hereinafter defined) for thecarbanion R_(T) with a compound of the formula Cp₂ Zr(H)Cl, wherein Cpis as previously defined. Typically, Cp represents an unsubstitutedcyclopentadienyl moiety, in which case the compound of the formula Cp₂Zr(H)Cl corresponds to the well-known Schwartz reagent forhydrozirconation. Alternatively, the zirconium intermediate may beprepared by other methods known per se.

In the above formulas, R_(T) represents an anionic ligand correspondingto a chain or cyclic array which it is desired to introduce into a finalproduct. As is well recognized in the art, an extremely wide variety ofligands for use in reactions such as 1,4-conjugate additions anddisplacements may be introduced into the known higher order reactivecuprate complexes of general formula I. In particular, the ligands R_(T)in accordance with the present invention comprise a broad range ofstructures that may be transferred in situ from a zirconate complex toreplace an alkyl ligand in a cuprate complex in accordance with themethod of the present invention. Exemplary classes of anionic ligandsare, for example, those discussed in the aforementioned U.S. Pat. No.4,777,275. Ligands R_(T) of interest include: alkyl, such as straight orbranched-chain alkyl and typically comprising one to about 20 carbonatoms, or cycloalkyl of three to about 20 carbon atoms; alkenyl, such asterminal and/or internal olefins and typically comprising two to about20 carbon atoms, or cycloalkenyl of three to about 20 carbon atoms;aryl, such as phenyl, naphthyl and phenanthryl; allylic; and benzylicmoieties.

Of particular interest for purposes of organic synthesis are thoseligands R_(T) which contain at least one unsaturation in the ligandcarbon chain. The electronic configuration of such ligands apparentlymakes them particularly susceptible to the desired transmetalation fromzirconium to copper. Ligands R_(T) selected from the group consisting ofterminal alkenyl, aryl, allylic and benzylic ligands are preferred foruse in accordance with the present invention.

The inventive method is of special utility in connection with ligandsR_(T) comprising the beta side chain of a natural or syntheticprostaglandin. In such side chains, any hydroxy groups present aregenerally protected from undesired side-reactions in a manner heretoforeknown per se (for example, by trialkylsilyl, tetrahydropyranyl ortetrahydrofuranyl moieties).

In accordance with the present invention, all of the aforesaid classesof ligands R_(T) include both the unsubstituted moieties and those whichare substituted by one or more non-interfering substituents. Bynon-interfering substituents is meant substituents which do not engagein undesirable side-reactions or rearrangements in the copper orzirconium complexes, and which do not hinder reaction due to stericand/or electronic factors. For example, suitable non-interferingsubstituents include alkyl, phenyl, alkoxy, phenoxy, halogen, andprotected hydroxy (i.e., a hydroxyl group which is protected by one of avariety of protective groups which are known per se) and the like. Inaddition, carbanions containing aldehyde, ketone and carboxyl functionalgroups which are suitably protected in a manner known per se maysuccessfully be employed in accordance with the inventive method [seeSchwartz et al., supra, at 339]. Typically, the substituents compriselower alkyl groups or derivatives thereof, wherein lower alkylrepresents straight- or branched-chain alkyl of one to six carbons orcycloalkyl of three to six carbon atoms. As the transmetalation may beeffected at reduced temperatures (for example, on the order of about-78° C.) and occurs rapidly, the inventive method provides theparticular advantage that various functionalities which might otherwisebe susceptible to undesired side-reactions during the reaction sequencesheretofore employed for preparation of reactive cuprate complexes (forexample, by a method as described in the aforementioned U.S. Pat. No.4,777,275) may be included in carbanions as prepared by atransmetalation process in accordance with the present invention.Similarly, the presence of non-interfering substituents on otherreactants employed in accordance with the inventive method has noadverse impact on the reaction mechanisms contemplated herein.

As previously noted, the zirconium intermediate of general formula IImay be prepared in a manner known per se, for example from a suitableligand precursor compound (e.g., an acetylene). In accordance with apreferred embodiment of the present invention, the provision of ligandR_(T) may suitably be carried out by selection of a ligand precursorcompound which provides the desired ligand via a hydrozirconationreaction with a compound of formula Cp₂ Zr(H)X in a manner known per se[see, e.g., Schwartz, J. et al., Angew. Chem. Int. Ed. Engl. 15(6), 333(1976)]. For example, reaction of a 1-alkynyl compound results in theformation of an intermediate comprising the corresponding 1-alkenylligand (i.e., a vinylzirconate); similarly, reaction of a 1-alkenylprecursor provides an intermediate comprising the corresponding alkylligand (i.e., an alkylzirconate). The use of non-terminal alkynyl oralkenyl carbanion precursor compounds generally results in the formationof zirconates by placement of the zirconium moiety at the stericallyleast hindered position of the precursor chain as a whole, for exampleby Zr-H addition to an internal multiple bond followed by rapidrearrangement via Zr-H elimination and readdition to place the metal ineach case at the less hindered position of the alkyl chain.Hydrozirconation of 1,3-dienes proceeds by 1,2-addition to thesterically less hindered double bond to give gamma, delta-unsaturatedalkylzirconium complexes in high yield; similarly, hydrozirconation ofconjugated enynes to produce dienylzirconium derivatives has also beenshown to proceed as predicted. In general, the products of suchreactions are determined by size exclusion phenomena based primarily onsteric effects. In some instances, the alternative procedures discussedsupra and/or other known procedures for preparation of the zirconiumcomplexes of general formula II (such as transmetalation or oxidativeaddition) may also suitably be employed to provide a particular anionicligand R_(T) (see, e.g., Negishi, E. et al., Synthesis, 1988, 1).

In a particularly preferred embodiment of the present invention, thezirconium intermediate of general formula II is prepared by reaction ofa compound of the formula Cp₂ Zr(H)Cl with a 1-alkynyl compound ofgeneral formula R-C.tbd.C-H, wherein R is selected from the groupconsisting of alkyl, alkenyl, aryl, allylic and benzylic moieties, saidmoiety being unsubstituted or substituted by non-interferingsubstituents. In this manner, it is possible to prepare higher ordercuprates comprising valuable vinylic ligands (for example, thosecorresponding to the beta side chains characteristic of prostaglandinanalogs) directly from the corresponding 1-alkynes. A particularadvantage of this preferred embodiment of the invention is that it isunnecessary to isolate the zirconium intermediate of general formula IIfrom the reaction mixture in which it is formed. Thus, in accordancewith this preferred embodiment of the inventive method, it is possibleto introduce a vinylic side chain into a target enone in a one-potreaction proceeding from the corresponding 1-alkyne.

After formation of the intermediate zirconate of general formula II, inaccordance with a particularly preferred procedure (reaction path A inScheme 1) addition to the reaction solution of one equivalent of R² Liis generally carried out at low temperatures (e.g., about -78° C.) toform the intermediate of general formula III. After cooling (for exampleto -78° C.), a cooled solution of R¹ ₂ Cu(A)Li₂ (prepared, for example,by the reaction of two equivalents of R¹ Li with CuCN in a suitablesolvent at -78° C.) is added and the solution allowed to stir at thistemperature for a relatively short period of time (e.g., approximately15 minutes). Following the transmetalation to form the mixed higherorder cuprate of general formula I, the reagent may be employed directlywithout isolation from the reaction medium. The alternative proceduresdescribed supra are also preferably carried out at reduced temperatures(i.e., generally below room temperature). Suitable solvents includetetrahydrofuran (THF), substituted tetrahydrofuran, dimethyl ether,diethyl ether, dimethoxyethane (DME), dimethyl sulfide (DMS), methylenechloride, toluene, benzene, dibutyl ether, t-butyl methyl ether, borontrifluoride and mixtures thereof.

Pursuant to a further preferred embodiment of the inventive method, thecuprate complex of general formula I is used as a source of an anionicligand R_(T) without isolation thereof from the reaction medium. Forexample, a target reactant for said anionic ligand may be added directlyto the reaction medium, so as to achieve a desired 1,4-conjugateaddition reaction, substitution reaction, etc. The cuprate complex ofgeneral formula I may suitably be used in the presence of one or moreadditives. Exemplary additives include Lewis acids, such as borontrifluoride etherate (BF₃.Et₂ O); silyl halides, such as trimethylsilylchloride (Me₃ SiCl); phosphines, such as tri-n-butylphosphine (D-Bu₃ P);amines, such as tetramethylethylenediamine, TMEDA (Me₂ NCH₂ CH₂ NMe₂);and various alkali metal salts, including halides and alkoxides (e.g.,lithium halides or alkoxides, LiX/LiOR).

As illustrated by the results reported in Table I, the method of thepresent invention permits the direct formation of mixed higher ordercuprates which selectively deliver a desired ligand to a target moleculewithout isolation of the reactive cuprates or intermediates in thepreparation thereof. Of particular interest is the introduction of betaside chains characteristic of prostaglandin analogs, such as that foundin the potent antisecretory agent misoprostol, without recourse tovinylic halide or stannane intermediates.

The invention will be better understood by reference to the followingexamples which are intended for purposes of illustration and are not tobe construed as in any way limiting the scope of the present invention,which is defined in the claims appended hereto.

EXAMPLE 1 Preparation of3-(1-t-Butyldiphenylsiloxy-2-propen-3-yl)-4-isopropylcyclohexanone

A 10 mL round-bottom flask equipped with a stir bar was charged withzirconocene chloride hydride (0.129 g, 0.50 mmol) and sealed with aseptum. The flask was evacuated with a vacuum pump and purged withargon, the process being repeated 3 times. THF (0.75 mL) was injectedand the mixture stirred to generate a white slurry which was treated viacanula with 1-t-butyldiphenylsiloxy-2-propyne (0.147 g, 0.50 mmol) as asolution in THF (0.75 mL). The mixture was stirred for 15 minutes toyield a nearly colorless solution which was cooled to -78° C. andtreated via syringe with ethereal MeLi (0.33 mL, 0.50 mmol) to generatea bright yellow solution. Depending upon the quality of the MeLi, theyield of isolated product may vary. Impurities (especially lithiumalkoxides) may have a detrimental impact. MeLi, available commerciallyin cumene-THF, may also be used in place of ethereal MeLi. Concurrently,CuCN (0.045 g, 0.50 mmol) was placed in a 5 mL round-bottom flaskequipped with a stir bar, and sealed under septum. The flask wasevacuated and purged with argon as above and DME (1.0 mL) added viasyringe. The resulting slurry was cooled to -78° C. and treated withMeLi in ether (0.66 mL, 1.0 mmol). The mixture was warmed to yield asuspension of Me₂ Cu(CN)Li₂ which was recooled to -78° C. and added viacanula to the zirconium solution. The mixture was stirred for 15 minutesat -78° C. to yield a bright yellow solution which was treated with4-isopropyl-2-cyclohexenone (0.037 mL, 0.25 mmol). After 10 minutes themixture was quenched with 10 mL of 10% NH₄ OH in saturated NH₄ Cl. Theproduct was extracted with 3×30 mL of ether and dried over Na₂ SO₄. Thesolution was then filtered through a pad of celite and the solventremoved in vacuo. The resulting residue was submitted to flashchromatography on silica gel (Petroleum Ether/Ethyl Acetate, 9/1) togive a quantitative yield (0.108 g) of3-(1-t-butyldiphenyl-siloxy-2-propen-3-yl)-4-isopropylcyclohexanone(product 1 in Table I) as a colorless oil which gave satisfactory IR,NMR, MS, and HRMS data.

EXAMPLE 2 Preparation of 3-(1-octen-1-yl)-cyclohexanone

A 10 mL round-bottom flask equipped with a stir bar was charged withzirconocene chloride hydride (0.129 g, 0.50 mmol) and sealed with aseptum. The flask was evacuated with a vacuum pump and purged withargon, the process being repeated 3 times. THF (1.5 mL) was injected andthe mixture stirred to generate a white slurry which was treated viacanula with 1-octyne (0.147 g, 0.50 mmol) The mixture was stirred for 15minutes to yield a nearly colorless solution which was cooled to -78° C.and treated via syringe with ethereal MeLi (0.35 mL, 0.50 mmol) togenerate a bright yellow solution. Concurrently, CuCN (0.045 g, 0.50mmol) was placed in a 5 mL round-bottom flask equipped with a stir bar,and sealed under septum. The flask was evacuated and purged with argonas above and THF (1.0 mL) added via syringe. The resulting slurry wascooled to -78° C. and treated with MeLi in ether (0.70 mL, 1.0 mmol).The mixture was warmed to yield a colorless solution of Me₂ Cu(CN)Li₂which was recooled to -78° C. and added via canula to the zirconiumsolution. The mixture was stirred for 15 minutes at -78° C. to yield ayellow solution which was treated with 2-cyclohexenone (0.024 mL, 0.25mmol). After 5 minutes the mixture was quenched with 5 mL of 10% NH₄ OHin saturated NH₄ Cl. The product was extracted with 3×20 mL of ether anddried over Na₂ SO₄. The solution was then filtered through a pad ofcelite and the solvent removed in vacuo. The resulting residue wassubmitted to flash chromatography on silica gel (Petroleum Ether/EthylAcetate, 9/1) to give an 86% yield (0.108 g) of3-(1-octen-1-yl)-cyclohexanone (product 2 in Table 1) as a colorless oilwhich gave satisfactory IR, NMR, MS, and HRMS data.

Using procedures analogous to those described in Examples 1 and 2, theproducts 3-6 of Table I are prepared from the corresponding educts andacetylenes and under the conditions indicated therein.

EXAMPLE 3 Preparation of misoprostol

A 10 mL round-bottom flask equipped with a stir bar was charged withzirconocene chloride hydride (0.129 g, 0.50 mmol) and sealed with aseptum. The flask was evacuated with a vacuum pump and purged withargon, the process being repeated 3 times. THF (1.50 mL) was injectedand the mixture stirred to generate a white slurry which was treatedwith trimethyl-[(1-methyl-1-(2-propynl)-pentyl)-oxy] silane (0.124 mL,0.50 mmol). The mixture was stirred for 15 minutes to yield a nearlycolorless solution which was cooled to -78° C. and treated via syringewith ethereal MeLi (0.35 mL, 0.50 mmol) to generate a bright yellowsolution Concurrently, CuCN (0.045 g, 0.50 mmol) was placed in a 5 mLround-bottom flask equipped with a stir bar, and sealed under septum.The flask was evacuated and purged with argon as above and ether (0.50mL) added via syringe. The resulting slurry was cooled to -78° C. andtreated with MeLi in ether (0.70 mL, 1.0 mmol). The mixture was warmedto yield a suspension of Me₂ Cu(CN)Li₂ which was recooled to -78° C. andadded via canula to the zirconium solution. The mixture was stirred for15 minutes at -78° C. to yield a bright yellow solution which wastreated via canula with methyl7-(5-oxo-3-[(triethylsilyl)-oxy]-1-cyclopenten-1-yl)-heptanoate (0.088mL, 0.25 mmol) in ether (0.50 mL). After 10 minutes the mixture wasquenched with 20 mL of 10% NH₄ OH in saturated NH₄ Cl. The product wasextracted with 3×30 mL of ether and dried over Na₂ SO₄. The solution wasthen filtered through a pad of celite and the solvent removed in vacuo.The resulting residue was submitted to flash chromatography on silicagel (Petroleum Ether/Ethyl Acetate, 9/1) to yield 0.132 g of theprotected form of misoprostol (product 7 in Table I) in a 92% yield as acolorless oil which was compared with authentic material.

EXAMPLE 4 Preparation of3-(1-Phenylethen-2-yl)-3,5,5-trimethylcyclohexanone

A 10 mL round-bottom flask equipped with a stir bar was charged withzirconocene chloride hydride (0.258 g, 1.0 mmol) and sealed with aseptum. The flask was evacuated with a vacuum pump and purged withargon, the process being repeated 3 times. THF (3.0 mL) was injected andthe mixture stirred to generate a white slurry which was treated viasyringe with phenyl acetylene (0.110 mL, 1.0 mmol). The mixture wasstirred for 15 minutes to yield a bright red solution which was cooledto -78° C. and treated via syringe with ethereal MeLi (1.40 mL, 2.0mmol). Concurrently, CuCN (0.0895 g, 1.0 mmol) was placed in a 5 mLround-bottom flask equipped with a stir bar, and sealed under septum.The flask was evacuated and purged with argon as above and THF (1.0 mL)added via syringe. The resulting slurry was cooled to -78° C. andtreated via canula with a solution of 2-thienyllithium prepared from themetalation of thiophene (0.080 mL, 1.0 mmol) with n-BuLi (0.43 mL, 1.0mmol) in THF (1.50 mL). The mixture was warmed to yield a suspension of(2-thienyl)Cu(CN)Li which was recooled to -78° C. and added via canulato the zirconium solution. The mixture was stirred for 30 minutes at-78° C. to yield a bright red solution which was treated with BF₃.Et₂ O(0.12 mL, 1.0 mmol) followed by the addition of isophorone (0.075 mL,0.5 mmol). After 1 hour the mixture was quenched with 10 mL of 10% NH₄OH in saturated NH₄ Cl. The product was extracted with 3×50 mL of etherand dried over Na₂ SO₄. The solution was then filtered through a pad ofcelite and the solvent removed in vacuo. The resulting residue wassubmitted to flash chromatography on silica gel (Petroleum Ether/EthylAcetate, 9/1) to give a 71% yield (0.086 g) of3-(1-phenylethen-2-yl)-3,5,5-trimethylcyclohexanone (product 3 in TableI) as a thick yellow oil which gave satisfactory IR, NMR, MS and HRMSdata. The above procedure can alternatively be carried out withcommercially-available (2-thienyl)Cu(CN)Li (2.94 mL, 1.0 mmol) whichwhen cooled to -78° C. can be added directly to the zirconium mixture.

EXAMPLE 5 Preparation of 3-(1-octen-1-yl)-cyclohexanone

A 10 mL round-bottom flask equipped with a stir bar was charged withzirconocene chloride hydride 0.258 g, 1.0 mmol) and sealed with aseptum. The flask was evacuated with a vacuum pump and purged withargon, the process being repeated 3 times. THF (2.0 mL) was injected andthe mixture stirred to generate a white slurry which was treated with1-octyne (0.148 mL, 1.0 mmol) as a solution in THF (0.75 mL). Themixture was stirred for 15 minutes to yield a yellow-orange solutionwhich was cooled to -78° C. and treated via canula with a THF (2.0 mL)solution of MeLi (2.71 mL, 3.0 mmol)/cumene to generate a bright yellowsolution Concurrently, CuCN (0.0895 g, 1.0 mmol) and LiCl (0.085 g, 2.0mmol) were placed in a 5 mL round-bottom flask equipped with a stir bar,and sealed under septum. The flask was evacuated and purged with argonas above and THF (3.0 mL) added via syringe. The mixture was stirred for5 minutes to generate a colorless homogeneous solution which was cooledto -78° C. and added via canula to the zirconium solution. The mixturewas stirred for 15 minutes at -78° C. to yield a bright yellow solutionwhich was treated with 2-cyclohexenone (0.048 mL, 0.50 mmol). After 10minutes the mixture was quenched with 10 mL of 10% NH₄ OH in saturatedNH₄ Cl. The product was extracted with 3×30 mL of ether and dried overNa₂ SO₄. The solution was then filtered through a pad of celite and thesolvent removed in vacuo. The resulting residue was submitted to flashchromatography on silica gel (Petroleum Ether/Ethyl Acetate, 9/1) togive a 73% yield (0.076 g) of 3-(1-octen-1-yl)-cyclohexanone (product 2in Table I) as a colorless oil which gave satisfactory IR, NMR, MS andHRMS data.

From the foregoing description, one skilled in the art can readilyascertain the essential characteristics of the invention and, withoutdeparting from the spirit and scope thereof, can adapt the invention tovarious usages and conditions. Changes in form and substitution ofequivalents are contemplated as circumstances may suggest or renderexpedient, and although specific terms have been employed herein, theyare intended in a descriptive sense and not for purposes of limitation.

                                      TABLE I                                     __________________________________________________________________________    Educt          Acetylene Conditions                                                                            Product       Yield (%)*                     __________________________________________________________________________        ##STR5##                                                                                  ##STR6## THF/DME -78°, 15 min                                                            ##STR7##     quant                          2                                                                                 ##STR8##                                                                                  ##STR9## THF/Et.sub.2 O -78°, 5 min                                                      ##STR10##    86                             3                                                                                 ##STR11##                                                                                 ##STR12##                                                                              THF, BF.sub.3 -78°, 1 h                                                         ##STR13##    71                             4                                                                                 ##STR14##                                                                                 ##STR15##                                                                              THF/Et.sub.2 O -78°, 10                                                         ##STR16##    81                             5                                                                                 ##STR17##                                                                                 ##STR18##                                                                              THF/Et.sub.2 O -60 to -50°, 1                                                   ##STR19##    50(71)**                       6                                                                                 ##STR20##                                                                                 ##STR21##                                                                              THF -78°, 3.5 h                                                                 ##STR22##    82                             7                                                                                 ##STR23##                                                                                 ##STR24##                                                                              THF/Et.sub.2 O -78°, 10                                                         ##STR25##    92                             __________________________________________________________________________     *Isolated, chromatographically pure materials; fully characterized by IR,     NMR, Mass spectrometry (High and Low Resolution).                             **Yield based on recovered starting material.                            

What is claimed is:
 1. A method for preparing a cuprate complex ofgeneral formula I ##STR26## wherein R_(T) is an anionic ligand forcarbon-to-carbon bond formation; R¹ is different from R_(T) and isselected from the group consisting of alkyl, alkenyl, alkynyl, allylic,aryl, benzylic and heterocyclic moieties, --BR³ wherein B is O or S andR³ is an alkyl, alkenyl, alkynyl, allylic, aryl, benzylic orheterocyclic moiety, and --NR⁴ R⁵ wherein R⁴ and R⁵ are the same ordifferent and each is an alkyl, alkenyl, alkynyl, allylic, aryl,benzylic or heterocyclic moiety, said moieties being unsubstituted orsubstituted by non-interfering substituents; and A is CN or SCN, whichcomprises:(a) reacting a zirconium intermediate of general formula II##STR27## wherein Cp represents a cyclopentadienyl moiety which isunsubstituted or substituted by non-interfering substituents, X ishalogen and R_(T) is as previously defined, with a compound of generalformula R² Li, wherein R² is defined in the same manner as R¹ and may bethe same as or different from R¹, to prepare an intermediate of generalformula III ##STR28## wherein R_(T) and R² are as previously defined;and (b) reacting the intermediate of general formula III with a cupratereagent of formula R¹ ₂ Cu(A)Li₂, wherein R¹ and A are as previouslydefined, both R¹ being the same or different, to provide the compound ofgeneral formula I via ligand exchange from zirconium to copper.
 2. Amethod according to claim 1, wherein R_(T) is an anionic ligand selectedfrom the group consisting of alkyl, alkenyl, aryl, allylic and benzylicligands, said ligand being unsubstituted or substituted bynon-interfering substituents.
 3. A method according to claim 2, whereinR_(T) is alkyl of one to about 20 carbon atoms.
 4. A method according toclaim 2, wherein R_(T) is alkenyl of two to about 20 carbon atoms.
 5. Amethod according to claim 4, wherein R_(T) is a 1-alkenyl moiety.
 6. Amethod according to claim 4, wherein R_(T) is a beta side chain of anatural or synthetic prostaglandin, wherein the hydroxy groups areoptionally protected.
 7. A method according to claim 1, wherein steps(a) and (b) are carried out without isolation of intermediates.
 8. Amethod according to claim 1, wherein step (b) is carried out below roomtemperature.
 9. A method according to claim 8, wherein step (b) iscarried out at about -78° C.
 10. A method according to claim 1, whereinsteps (a) and (b) are carried out in a solvent selected from the groupconsisting of tetrahydrofuran, substituted tetrahydrofuran, dimethylether, diethyl ether, dimethoxyethane, dimethyl sulfide, methylenechloride, toluene, benzene, dibutyl ether, t-butyl methyl ether, borontrifluoride and mixtures thereof.